Ideally, a sustained release dosage form should deliver the medicament at a constant rate throughout the gastrointestinal tract. With many of the delivery systems currently available, this expectation may not be realized since many drugs which are weakly acidic or basic exhibit solubility which varies in relation to pH. A decline in solubility in response to pH fluctuations within the body may result in a decreased release rate if the formulation does not respond with an appropriate change in its permeability characteristics.
The use of hydrophilic matrices to provide sustained drug release is known. Christenson et al. in U.S. Pat. No. 3,065,143 disclose the use of certain hydrophilic gums, including hydroxypropyl methylcelluloses, in the preparation of sustained release tablets. Hill in U.S. Pat. No. 3,458,622 describes the preparation of sustained release tablets using a combination of povidone and carbopol. Weiss et al. in U.S. Pat. No. 4,252,786 describe a controlled release tablet consisting of a core tablet which was identical to the tablet disclosed in Hill, that is, containing an active ingredient, povidone, and carbopol. A coating consisting of a hydrophobic and a hydrophilic polymer was employed to prevent the initial burst of drug release encountered with this tablet. Schor et al. in U.S. Pat. No. 4,389,393 describe sustained release therapeutic compositions based on high molecular weight hydroxypropyl methylcellulose. Guley et al. in U.S. Pat. No. 4,309,405 describe a sustained release pharmaceutical composition comprising a compressed core, a seal coating surrounding the core and a sugar coating surrounding the seal coated core wherein, a) the core consists of an active ingredient, at least one pharmaceutically acceptable water soluble polymer selected from the group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, xanthan gum and karaya gum, and at least one pharmaceutically acceptable water insoluble polymer mixture selected from the group consisting of ethylcellulose and at least one of carboxypolymethylene, hydroxypropyl methylcellulose phthalate and hydroxypropyl cellulose, said polymers in an amount of about 30% to 72% by weight of the core; b) the seal coating comprises a film coating selected from the group consisting of enteric and non-enteric materials and mixtures thereof; and c) the sugar coating comprises sugar and a loading dose of said drug contained in the core. Dunn in U.S. Pat. Nos. 4,522,804, 4,521,402 and 4,521,401 describes constant order release solid oral. dosage formulations comprising an active ingredient, from about 0.5 to 6.0% of an acid-retardant or hydrophobic cellulose derivative, from about 2.5 to 35% of a hydrogenated vegetable oil, from about 1 to 20% of carbopol, from about 0.5 to 4.0% of fumed silicon dioxide and from about 0.4 to 3.0% of a lubricant.
Conventional hydrogels such as those based on high viscosity hydroxypropyl methylcelluloses are known to deliver medicaments at a constant rate independent of pH in relation to the hydration, gel viscosity and relative permeability of the dosage form. This, however, does not ensure that a drug whose solubility varies significantly as a function of pH will be delivered at a constant rate throughout the gastrointestinal pH range. With these conventional hydrogel formulations, the rate of drug release will be directly related to the solubility of the drug. If the drug possesses greater solubility in gastric fluids as compared to intestinal fluids, a characteristic of many weakly basic active ingredients, one would expect the release rate of the matrix to be faster in gastric fluids, than when the formulation makes the transition into the small intestine where the pH values are reported to be higher. For these formulations, if the dosage form is not retained for an adequate time period in the stomach, the decrease in drug release rate encountered in the intestine might result in incomplete bioavailability and greater variability from patient to patient.
Film coatings are known to have the ability to modify the release pattern of a drug once applied to pharmaceutical products. One type of film coating, known as an enteric coating, is used to prevent the release of drugs in, or protect drugs from, the effects of the gastric environment. Enteric coatings are used to delay the release of drugs which are inactivated by the stomach contents or which cause gastric irritation.
The matrix compositions of the present invention differ from existing formulations in that the present compositions have been designed to respond to increases in pH with a corresponding increase in the permeability of the dosage form. This allows the dosage form to release the active ingredient at an appropriate rate throughout the gastrointestinal tract.